Inclusion body myositis: new insights into pathogenesis.
OBJECTIVE
The pathogenesis of sporadic inclusion body myositis is complex and the disease has a relentless course. Recent observations regarding possible mechanisms of disease may provide targets for therapy.


RESULTS
Evidence is strengthening that specific T-cell and B-cell responses are ongoing in skeletal muscle in sporadic inclusion body myositis and that cytokines and chemokines generated by an autoimmune response are likely to influence antigen presentation by intramuscular dendritic cells and muscle cells, expression of amyloid precursor protein and the endoplasmic reticulum stress response. Early beta-amyloid expression and perhaps aberrant expression of protein processing enzymes, such as E3 ligases, seem to be involved in the myopathic process. NF-kappaB activation by endoplasmic reticulum stress and cytokine action further stimulates amyloid precursor protein production, exacerbates endoplasmic reticulum stress and increases myostatin content in muscle contributing to muscle atrophy.


CONCLUSIONS
Understanding the paradoxes in sporadic inclusion body myositis is important in determining rational therapy for the disease. Amyloid precursor protein is expressed in muscle in other inflammatory muscle diseases but the cellular distribution differs and inclusions do not form so that other metabolic defects seem to be important. Intramuscular immune cells influence muscle function and viability in inclusion body myositis but immunotherapy is ineffective. A useful target for therapy may be restoration of muscle regenerating capacity.
Garlepp
Michael J
MJ
School of Pharmacy, Curtin University of Technology, Australia. mgarlepp@ichr.uwa.edu.au
Mastaglia
Frank L
FL
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D018979:Myositis, Inclusion Body / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012038:Regeneration; D013601:T-Lymphocytes / Q000276:immunology
D016229:Amyloid beta-Peptides; D016207:Cytokines; D009124:Muscle Proteins